Up date on malaria vaccine
Dr Walter Otieno
MBChB, M. Med (Paeds), PhD
Mark R. Withers, M.D., MPH,
Director, WRP Kombewa Clinic
Walter Reed Project-Centre for Clinical Research
Kenya Medical Research Institute
WRP-Kisumu
2 2
WRP-Kisumu: 4 main campuses
 Kisumu HQ (“Kondele”)
• Administration
• Basic science: ELISA, PCR, flow cyt, RDTs
• New Nyanza Provincial General Hospital (PGH, Russian)
– Children’s Hospital: 65 bed facility
– Ward 8: dedicated in-out patient clinical research center
 “Center of Excellence” for malaria microscopy
 KEMRI “Center for Global Health” (Kisian town)
• Entomology
• malaria culture lab (monitors drug resistance patterns)
 Kombewa Clinical Research Center
• Dedicated unit for large clinical trials
3
Malaria Vaccine Development
• Ongoing for P. falciparum & P. vivax
• Theoretical Concepts:
– Pregnant women protect newborns
– Living in endemic areas develop immunity
• Malaria vaccines target the life cycle:
– Pre-erythrocytic stage (sporozoite/hepatic)
– Erythrocytic (asexual) stage
– Sexual stage (transmission blocking)
TARGETS OF MALARIA
VACCINES
• Pre-erythrocytic
-Prevent infection
-Reduce disease
• Blood-stage
-Prevent disease
• Transmission
blocking
-Prevent
transmission
RTS,S Program History
Circumsporozoite protein
 Most abundant protein covering entire sporozoite
surface
 Also expressed by malaria liver stages
 Structure of CS protein:
– Of all malaria species has a central domain
with several amino acid repetitions
– Amino acid sequence that composes each
repetition is completely different for each
plasmodium species
Circumsporozoite protein
• Structure of CS protein:
– P. falciparum CS protein has limited variability
therefore ideal for vaccines
– P. vivax isolates display enormous variationtherefore not ideal for malaria vaccines
– Amino acid repetitions targets for antibodies
– N- & C-terminals contain epitopes recognized
by CD4 & CD8 T cells
– T cells specific for epitopes of CS protein
confer protective immunity against liver stages
RTS,S Malaria Vaccine Development
 Pre-erythrocytic stage vaccine
 Composition of vaccine antigen:
 Sequence of circumsporozoite protein
 Hepatitis B surface antigen (HBsAg)
 Adjuvants: ASO2 & ASO1
 HBsAg is encoded with hepatitis B
virus S protein gene, therefore
protects against hepatitis B.
RTS,S Malaria Vaccine Development…
• Goal: develop 80% efficacious vaccine by 2025
with ≥4 year protection
• Characteristics of an ideal vaccine:
–
–
–
–
–
Safe
Effective
Affordable
Easy to deliver (EPI delivery system)
Will not interfere with other EPI vaccines
DEVELOPMENT OF THE RTS,S MALARIA
VACCINE
SPOROZOITE STAGE OF MALARIA PARASITE
DEVELOPMENT OF RTS,S
MALARIA VACCINE
HEP-B VIRUS
SPOROZOITE
R (REPEAT)
R
+
T (T-CELL)
T
S
S (HEP-B)
+
S
STRUCTURE OF THE CIRCUMSPOROZOITE
PROTEIN (CSP)
N -TERMINAL
C -TERMINAL
T-CELL EPITOPES
CENTRAL REPEAT REGION
DEVELOPMENT OF RTS,S
MALARIA VACCINE
SPOROZOITES – ARE COATED WITH A
SURFACE PROTEIN –
CIRCUMSPOROZOITE PROTEIN (CSP)
A SEGMENT OF THE
CIRCUMSPOROZOITE PROTEIN
CONTAINING REPEAT (R) AND TCELL EPITOPES (T) IS FUSED TO
HEPATITIS B SURFACE ANTIGEN (S)
TO PRODUCE FUSION PROTEIN,
RTS
RTS IS COMBINED WITH A
SECOND UNFUSED HEPATITIS B
SEGMENT (S) TO FORM A STABLE
RTS,S ANTIGEN
RESULTS OF RTS,S MALARIA
VACCINE TRIALS
• Many trials have shown that RTS,S malaria
vaccine is safe and immunogenic
• RTS,S efficacy trial in Mozambique – enrolled
2022 children aged 1-4 years
• 50% protection against severe malaria and
severe anemia at 42 months post vaccination
RESULTS OF RTS,S MALARIA
VACCINE TRIALS
• Many trials have shown that RTS,S malaria vaccine is
safe and stimulates the immune system
• RTS,S efficacy trial in Mozambique – enrolled 2022
children aged 1-4 years
• 50% protection against severe malaria and severe
anemia
• Malaria causes 1 million childhood deaths per year in
Africa
• If this vaccine could reduce by half the cases of severe
disease, we would be saving thousands of lives
MAIN OBJECTIVES
• To investigate efficacy against clinical
disease in children 5-17 months of age
and
• Infants 6-12 weeks of age who receive the
vaccine co-administered with EPI vaccines
ON GOING RTS,S VACCINE TRIAL
• A multi-center, Phase III trial of the candidate malaria
vaccine RTS,S
• The trial has been designed to address key safety and
efficacy information required before a vaccine can be
licensed
•
Across 11 sites in Africa with different levels of malaria
transmission; Kenya, Tanzania, Mozambique, Gabon,
Ghana, Burkina Faso
How does RTS, S work?
• RTS,S induces the production of
antibodies and T cells that are believed to
diminish the malaria parasite’s ability to
infect, develop, and survive in the human
liver.
DESIGN OF THE TRIAL
Children 5-17 months of age
Vaccination at 0, 1, 2 months
Boost at month 20
RTS,S
RTS,S
RTS,S
Control Vaccine
Control vaccine
Control Vaccine
Children 6-12 weeks of age
Vaccination at 0, 1, 2 months
Boost at month 20
RTS,S + EPI VACCINE
RTS,S
RTS,S/AS01E + EPI VACCINE
CONTROL VACCINE
CONTROL VACCINE + EPI VACCINE
CONTROL VACCINE
Thank you